Obesity is associated with chronic inflammatory signaling, which has been implicated in the pathogenesis of various human diseases, including type 2 diabetes (see Saltiel). Noting that fatty acids signal through G protein–coupled receptors (GPCRs) and that ω-3 fatty acids can have anti-inflammatory effects, Oh et al. investigated the expression patterns of GPCRs that sense fatty acids and found that both adipocytes and macrophages showed abundant GPR120 mRNA. Moreover, the abundance of GPR120 mRNA in macrophages from adipose tissue and liver increased in mice fed a high-fat diet. The GPR120 agonist GW9508 inhibited inflammatory responses to lipopolysaccharide (LPS) activation of Toll-like receptor 4 (TLR4) in RAW 264.7 monocytic cells, including phosphorylation of IKKβ [a constituent of the nuclear factor κB (NF-κB) pathway] and JNK (c-Jun N-terminal kinase), degradation of IκB (inhibitor of NF-κB), and secretion of TNF-α (tumor necrosis factor–α) and interleukin 6. These anti-inflammatory effects were blocked by GPR120 knockdown, as was inhibition by the ω-3 fatty acid docosohexanoic acid (DHA) of inflammatory signaling mediated by TNF-α or TLRs. The ability of DHA to antagonize LPS signaling was also blocked by knockdown of β-arrestin2 but not that of Gαq/11, and immunocytochemical analysis of HEK293 cells transfected with labeled forms of GPR120 and β-arrestin2 revealed that DHA promoted the translocation of β-arrestin2 to the cell membrane, where it colocalized with GPR120 before their internalization. DHA inhibited LPS-dependent phosphorylation of TAK1 (transforming growth factor–β activated kinase 1) and MKK4 (mitogen-activated protein kinase kinase 4) in RAW 264.7 cells, as well as the LPS-dependent coimmunoprecipitation of TAK1 binding protein 1 (TAB1) with TAK1, whereas it promoted coimmunoprecipitation of TAB1 with β-arrestin2. In 3T3-L1 adipocytes, DHA stimulated 2-deoxyglucose (2-DOG) uptake and translocation of the glucose transporter GLUT4 to the plasma membrane; its stimulation of 2-DOG uptake depended on GPR120, Gαq/11, and GLUT4 but not β-arrestin2. Mice lacking GPR120 (GPR120 KO mice) were insulin resistant when fed a diet of normal chow and, unlike wild-type mice, failed to show beneficial effects on insulin sensitivity and hepatic lipid metabolism of fish oils high in ω-3 fatty acids when fed a high-fat diet. Bone marrow transplants indicated that these in vivo effects of GPR120 KO depended predominantly on macrophages. Indeed, analyses of adipose tissue in wild-type and GPR120 KO mice indicated that a high-fat diet promoted accumulation of inflammatory macrophages in adipose tissue and that this was inhibited by ω-3 fatty acid signaling through GPR120. Moreover, DHA signaled through GPR120 to inhibit macrophage chemotaxis toward adipocyte-conditioned medium or monocyte chemotactic protein-1. The authors thus conclude that ω-3 fatty acids signal through GPR120 to reduce inflammation and promote insulin sensitivity.